Blockade of innate inflammatory cytokines TNFα, IL-1β, or IL-6 overcomes virotherapy-induced cancer equilibrium to promote tumor regression.

IF 4.1 Q2 IMMUNOLOGY
Immunotherapy advances Pub Date : 2023-07-03 eCollection Date: 2023-01-01 DOI:10.1093/immadv/ltad011
Michael J Walsh, Lestat R Ali, Patrick Lenehan, Courtney T Kureshi, Rakeeb Kureshi, Michael Dougan, David M Knipe, Stephanie K Dougan
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Abstract

Cancer therapeutics can lead to immune equilibrium in which the immune response controls tumor cell expansion without fully eliminating the cancer. The factors involved in this equilibrium remain incompletely understood, especially those that would antagonize the anti-tumor immune response and lead to tumor outgrowth. We previously demonstrated that continuous treatment with a non-replicating herpes simplex virus 1 expressing interleukin (IL)-12 induces a state of cancer immune equilibrium highly dependent on interferon-γ. We profiled the IL-12 virotherapy-induced immune equilibrium in murine melanoma, identifying blockade of innate inflammatory cytokines, tumor necrosis factor alpha (TNFα), IL-1β, or IL-6 as possible synergistic interventions. Antibody depletions of each of these cytokines enhanced survival in mice treated with IL-12 virotherapy and helped to overcome equilibrium in some tumors. Single-cell RNA-sequencing demonstrated that blockade of inflammatory cytokines resulted in downregulation of overlapping inflammatory pathways in macrophages, shifting immune equilibrium towards tumor clearance, and raising the possibility that TNFα blockade could synergize with existing cancer immunotherapies.

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阻断先天性炎性细胞因子TNFα、IL-1β或IL-6可克服病毒治疗诱导的癌症平衡,促进肿瘤消退。
癌症疗法可以导致免疫平衡,其中免疫反应控制肿瘤细胞的扩展,而不完全消除癌症。参与这种平衡的因素仍不完全清楚,尤其是那些会拮抗抗肿瘤免疫反应并导致肿瘤生长的因素。我们之前证明,用表达白细胞介素(IL)-12的非复制性单纯疱疹病毒1持续治疗可诱导高度依赖干扰素-γ的癌症免疫平衡状态。我们描述了IL-12病毒治疗诱导的小鼠黑色素瘤免疫平衡,确定阻断先天性炎性细胞因子、肿瘤坏死因子α(TNFα)、IL-1β或IL-6可能是协同干预措施。这些细胞因子中每一种的抗体耗竭增强了用IL-12病毒治疗的小鼠的存活率,并有助于克服某些肿瘤中的平衡。单细胞RNA序列显示,炎症细胞因子的阻断导致巨噬细胞中重叠炎症途径的下调,将免疫平衡转移到肿瘤清除,并增加了TNFα阻断与现有癌症免疫疗法协同作用的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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